SFARI Research Highlights
Highlights of SFARI-funded papers, selected by the SFARI science team.
SFARI Investigators Gaia Novarino and Joseph Gleeson previously reported that reductions in the brain levels of branched-chain amino acids (BCAAs) can lead to autism spectrum disorder (ASD) (Novarino et al., 2012). BCAAs, comprising valine, leucine and isoleucine, need to be constantly taken up from the periphery to ensure proper brain functioning. Here, Novarino, Gleeson and their colleagues asked whether the amino acid transporter LAT1, located at the blood brain barrier, plays a critical role in transporting BCAAs into the brain. To do this, the researchers studied a mouse model in which SLC7A5, the gene encoding LAT1, was deleted from the blood brain barrier. Both newborn and adult mice exhibited decreases in brain BCAA levels and displayed behavioral alterations, including motor delays and ASD-related phenotypes. Injection of BCAAs into the brains of adult mice was found to rescue some of these behaviors. Novarino and Gleeson had previously identified mutations in BCKDK — a gene whose encoded protein is responsible for the production of BCAAs — in several individuals with ASD (Novarino et al., 2012). In the current study, they identified two independent families with multiple children affected by ASD and who harbored function-disrupting mutations in SLC7A5. Combined, these findings suggest that restoring appropriate brain levels of BCAAs could potentially improve outcomes in a subset of individuals with ASD.
Tarlungeanu D.C., Deliu E., Dotter C.P., Kara M., Janiesch P.C., Scalise M., Galluccio M., Tesulov M., Morelli E., Sonmez F.M., Bilguvar K., Ohgaki R., Kanai Y., Johansen A., Esharif S., Ben-Omran T., Topcu M., Schlessinger A., Indiveri C., Duncan K.E., Caglayan A.O., Gunel M., Gleeson J.G., Novarino G. Impaired amino acid transport at the blood brain barrier is a cause of autism spectrum disorder. Cell 167, 1481–1494 (2016) PubMed
Progress in the development of new treatments for autism has been hampered by a lack of sensitive and objective ways to benchmark treatment success. SFARI Investigator Pamela Ventola and colleagues now report on their identification of functional magnetic imaging (fMRI) biomarkers that allow accurate predictions of intervention success. Ventola and colleagues imaged 20 high-functioning children with autism while they viewed video clips of individuals performing natural movements relevant to early childhood experiences, such as playing pat-a-cake, or scrambled video clips. The brain imaging data was then related to the children’s responses after they had participated in 16 weeks of pivotal response treatment (PRT), an evidence-based behavioral intervention that is focused on social communication skill development. In doing this, the researchers identified a number of fMRI signatures in brain regions supporting social information processing and social motivation that predicted the success of PRT, providing key predictive biomarkers for treatment intervention in young children with autism. In a related SFARI-funded project, Ventola and colleagues are studying whether responses to this treatment can also be accurately assessed using eye-tracking tools.
Yang D., Pelphrey K.A., Sukhodolsky D.G., Crowley M.J., Dayan E., Dvornek N.C., Venkataraman A., Duncan J., Staib L., Ventola P. Brain responses to biological motion predict treatment outcome in young children with autism. Transl Psychiatry 6, e948 (2016) PubMed
Studies of cohorts that consist primarily of individuals of European descent, such as the Simons Simplex Collection and the Autism Sequencing Consortium, have found that de novo mutations significantly contribute to risk for autism spectrum disorders (ASD). SFARI Investigator Evan Eichler and his colleagues now report on their assessment of de novo mutations in a cohort of over 1,500 Chinese individuals with ASD from the Autism Clinical and Genetic Resources in China (ACGC). The researchers used molecular inversion probes to selectively sequence the coding regions of 189 candidate ASD risk genes. Their results establish the importance of de novo mutations for conferring autism risk in both European and Chinese populations. SCN2A was found to be the most prevalent gene for de novo mutations in this study, confirming its role as a high-confidence autism risk gene. They also found robust evidence of ASD risk conferred by a number of candidate genes previously associated with only minimal mutation occurrence. Furthermore, Eichler and colleagues re-contacted individuals with de novo mutations, allowing them to not only confirm previously published genotype-phenotype correlations but also to describe potentially new genetic subtypes of ASD. Taken together, the findings from this study highlight how large global cohorts are likely to provide valuable insights into the genetic architecture of autism.
Wang T., Guo H., Xiong B., Stessman H.A., Wu H., Coe B.P., Turner T.N., Liu Y., Zhao W., Hoekzema K., Vives L., Xia L., Tang M., Ou J., Chen B., Shen Y., Xun G., Long M., Lin J., Kronenberg Z.N., Peng Y., Bai T., Li H., Ke X., Hu Z., Zhao J., Zou X., Xia K., Eichler E.E. De novo genic mutations among a chinese autism spectrum disorder cohort. Nat. Commun. 7, 13316 (2016) PubMed
Genetic mechanisms underlying physical trait differences between males and females contribute to sex bias in autism
Males are 4.5 times more likely to be affected by autism spectrum disorder (ASD) than females. Recent findings of a higher burden of rare de novo loss-of-function mutations in females have lent support to the “female protective model” for ASD; however, whether such a model also applies to common risk factors for ASD remains to be determined. In the current study, SFARI Investigator Lauren Weiss and colleagues examined single nucleotide polymorphism (SNP) data from numerous ASD datasets, including the Simons Simplex Collection, and evaluated a number of different genetic models that could plausibly generate sex bias. They found no differences between males and females in overall SNP genetic load, in SNPs affecting gene expression levels within the brain or in SNPs affecting levels of sex hormones within these datasets. Their data did, however, support a role for SNP heterogeneity on the X chromosome in contributing to the sex bias observed in ASD. Interestingly, they also found that a substantial number of these SNPs are associated with the regulation of physical differences between the sexes, such as height, weight and waist measurements. These data suggest that genetic mechanisms regulating general differences in sex characteristics — as opposed to brain- or behavior-specific origins for sex differences — contribute to ASD susceptibility. Further, these results reinforce the importance of considering each component of the genetic architecture (e.g., rare variants, common polymorphisms) separately when assessing sex-specific mechanisms in ASD.
Mitra I., Tsang K., Ladd-Acosta C., Croen L.A., Aldinger K.A., Hendren R.L., Traglia M., Lavillaureix A., Zaitlen N., Oldham M.C., Levitt P., Nelson S., Amaral D.G., Herz-Picciotto I., Fallin M.D., Weiss L.A. Pleiotropic mechanisms indicated for sex differences in autism. PLOS Genet. 12, e1006425 (2016) PubMed